Thanks to dopamine, brownies are in the eye of the beholder

Activity in the eyes seems to reflect what's going on in the brain.

We all need to eat. But for humans, food does more than keep up alive; it makes us happy, serves as a reward, and often gives us something to look forward to.

Dopamine is intimately involved in our relationship with food, since this neurotransmitter plays a major role in the reward and pleasure circuitry of our brains. It spikes when we are exposed to (or even merely anticipating) something we like, and it is known to be involved in addictive behavior. Understanding changes in the brain’s dopamine signaling can shed light on how and why we experience pleasure, but measuring these changes is expensive and invasive. Currently, researchers use PET scans to assess dopamine-related responses in the brain, but a single scan costs about $2,000 and can take over an hour to complete.

However, dopamine isn’t limited to the brain; there are other dopamine pathways in the body, including circuitry in the retinas, heart, and kidneys. A group of researchers wondered whether dopamine levels in these other pathways might change in concert with those in the brain. Using an inexpensive ophthalmologic technique called electroretinography, or "ERG," they tested whether dopaminergic responses in the retina reflect reward-related neurotransmitter activity in the brain. Their results are published in the latest issue of the journal Obesity.

ERG is a relatively simple procedure that quantifies the responses of light-sensitive cells in the retina. During the procedure, light is flashed into a person’s eye and a machine measures the resulting dopamine-driven electrical responses. If dopamine pathways in the brain and retina are indeed linked, the signals picked up by the ERG should spike in response to the subject getting a reward, just as dopamine levels in the brain do.

Over four days, subjects in the study ingested four different stimuli: a chocolate brownie, water, and two different doses of methylphenidate, a known dopamine agonist. After each stimulus, the researchers conducted an ERG to assess the electrical activity in the retina. In large doses, methylphenidate is known to produce dopamine spikes in the brain, so the first order of business was to determine whether a similar peak in activity was seen in the retina.

Indeed it was; when the subjects ingested the larger of the two doses of methylphenidate, the ERG measured a significant increase in the electrical signals in the retina. This suggests that the dopamine activity in a person’s retina can reflect the dopamine activity in their brain. When the subjects ate the brownie, the researchers observed an equivalent spike in the retinas' electrical activity, demonstrating that it's possible to effectively measure the brain’s pleasure response to a food reward simply via a person’s eyes.

This is a pretty exciting finding, since ERG is a much cheaper and easier technique than PET scanning, at about $150 for a set of 200 scans. The study was essentially a proof-of-concept, since there were only nine participants and the subjects were very homogenous—none were on prescription medication, had depression or diabetes, or smoked. However, the results are both surprising and exciting, as there was no previous evidence that the dopamine pathways in the eyes and brain were synchronized. Understanding the reward circuitry in the brain has implications for understanding addictive behavior, nutrition, and obesity, and ERGs could help make research in these areas easier and more fruitful.

The article erroneously states that methylphenidate (Ritalin) is a dopamine antagonist (something that reduces the activity of dopamine receptors). This would be bizarre, as increased dopamine increases alertness.

Methylphenidate is a dopamine agonist, by acting as a dopamine-norepinephrine reuptake inhibitor. This means that the dopamine transporters are "captured" by Ritalin molecules, preventing them from latching on to dopamine molecules and bringing them back to the synapse for recycling.

With a parent currently in his 5th year of Parkinson's disease which is linked to the inability to create dopamine you come to appreciate the vital role dopamine plays in the human body. To witness the effects of the lack of dopamine on your parent is truly heartbreaking so the more that can be learned and understood about the dopamine pathways and the role it plays in the human body can only improve the chances of further drug development to combat this terrible disease.

The article erroneously states that methylphenidate (Ritalin) is a dopamine antagonist (something that reduces the activity of dopamine receptors). This would be bizarre, as increased dopamine increases alertness.

Methylphenidate is a dopamine agonist, by acting as a dopamine-norepinephrine reuptake inhibitor. This means that the dopamine transporters are "captured" by Ritalin molecules, preventing them from latching on to dopamine molecules and bringing them back to the synapse for recycling.

Edit: looks like it was edited after your post. I suppose you could argue that the change you suggested made it less wrong, but it is still incorrect.

I would suggest that "acts similarly to a dopamine agonist because it is a dopamine-norepinephrine reuptake inhibitor" is more correct than to say that it is an agonist. Simply calling it what it is, a re-uptake inhibitor, would probably be better. While it is functionally equivalent in terms of the effects on the user in this case, the means of action is distinct - increasing dopamine levels by blocking re-uptake as opposed to mimicking dopamine directly.

That is to say, it is not technically an agonist at all because it does not bond to a receptor but instead occupies a transporter.

An agonist actually mimics a neurotransmitter when it binds to a receptor.

Ritalin (methylphenidate) is a norepinephrine-dopamine reuptake inhibitor (more effective with norepinephrine than dopamine) and works by keeping norepinephrine and dopamine in the synaptic gap longer than it normally would have.

An agonist actually mimics a neurotransmitter when it binds to a receptor.

Ritalin (methylphenidate) is a norepinephrine-dopamine reuptake inhibitor (more effective with norepinephrine than dopamine) and works by keeping norepinephrine and dopamine in the synaptic gap longer than it normally would have.

Yep which is why unknowingly combining a dopamine reuptake-inhibitor with a dopamine agonist can be particularly problematic and is not strictly an additive effect, part of the reason why the distinction is important.

An agonist actually mimics a neurotransmitter when it binds to a receptor.

Ritalin (methylphenidate) is a norepinephrine-dopamine reuptake inhibitor (more effective with norepinephrine than dopamine) and works by keeping norepinephrine and dopamine in the synaptic gap longer than it normally would have.

Yep which is why unknowingly combining a dopamine reuptake-inhibitor with a dopamine agonist can be particularly problematic and is not strictly an additive effect, part of the reason why the distinction is important.

Just to beat an almost dead horse: I am wondering where the mistake was made (in the study or in the article) because if its the study presumes this, it renders a major "finding" highly questionable.

An agonist actually mimics a neurotransmitter when it binds to a receptor.

Ritalin (methylphenidate) is a norepinephrine-dopamine reuptake inhibitor (more effective with norepinephrine than dopamine) and works by keeping norepinephrine and dopamine in the synaptic gap longer than it normally would have.

Yep which is why unknowingly combining a dopamine reuptake-inhibitor with a dopamine agonist can be particularly problematic and is not strictly an additive effect, part of the reason why the distinction is important.

Just to beat an almost dead horse: I am wondering where the mistake was made (in the study or in the article) because if its the study presumes this, it renders a major "finding" highly questionable.

Not necessarily because both (agonist and reuptake-inhibitor) would cause increases effects equivalent to increased availability and utility of dopamine. Additionally a re-uptake inhibitor would actually be preferable in this sort of experiment because it does not involve introducing a dopamine analog and instead increases availability and utility of the actual dopamine in your nervous system. The can also potentially be made to last longer and far more evenly and consequently make the "spike" easier to measure by both the ERG and a pet scan. That means its at least possible to correlate the measurements made by the ERG with the scans of the brain made by the far slower PET scan even for the same patient. So even if the paper misidentified the drug as either an agonist or antagonist, the drug they used was probably the most appropriate.

The article erroneously states that methylphenidate (Ritalin) is a dopamine antagonist (something that reduces the activity of dopamine receptors). This would be bizarre, as increased dopamine increases alertness.

Methylphenidate is a dopamine agonist, by acting as a dopamine-norepinephrine reuptake inhibitor. This means that the dopamine transporters are "captured" by Ritalin molecules, preventing them from latching on to dopamine molecules and bringing them back to the synapse for recycling.

Edit: looks like it was edited after your post. I suppose you could argue that the change you suggested made it less wrong, but it is still incorrect.

I would suggest that "acts similarly to a dopamine agonist because it is a dopamine-norepinephrine reuptake inhibitor" is more correct than to say that it is an agonist. Simply calling it what it is, a re-uptake inhibitor, would probably be better. While it is functionally equivalent in terms of the effects on the user in this case, the means of action is distinct - increasing dopamine levels by blocking re-uptake as opposed to mimicking dopamine directly.

That is to say, it is not technically an agonist at all because it does not bond to a receptor but instead occupies a transporter.

This is true. However, agonist is also used more loosely to mean "increases the activity at a receptor". I wanted to focus on the specific issue with the word "antagonist", because I believe Kate likely knows the difference between an agonist and a reuptake inhibitor. I wanted to cut her some slack. There are a ton of terms in my own field (software engineering) with very specific meaning, but in casual conversation with other developers those words get used much more loosely.

Disclaimer: This post is in no way criticizing your desire to clarify the issue further - thanks for your contribution! I'm just saying why I chose not to be as particular.

The article erroneously states that methylphenidate (Ritalin) is a dopamine antagonist (something that reduces the activity of dopamine receptors). This would be bizarre, as increased dopamine increases alertness.

Methylphenidate is a dopamine agonist, by acting as a dopamine-norepinephrine reuptake inhibitor. This means that the dopamine transporters are "captured" by Ritalin molecules, preventing them from latching on to dopamine molecules and bringing them back to the synapse for recycling.

Edit: looks like it was edited after your post. I suppose you could argue that the change you suggested made it less wrong, but it is still incorrect.

I would suggest that "acts similarly to a dopamine agonist because it is a dopamine-norepinephrine reuptake inhibitor" is more correct than to say that it is an agonist. Simply calling it what it is, a re-uptake inhibitor, would probably be better. While it is functionally equivalent in terms of the effects on the user in this case, the means of action is distinct - increasing dopamine levels by blocking re-uptake as opposed to mimicking dopamine directly.

That is to say, it is not technically an agonist at all because it does not bond to a receptor but instead occupies a transporter.

This is true. However, agonist is also used more loosely to mean "increases the activity at a receptor". I wanted to focus on the specific issue with the word "antagonist", because I believe Kate likely knows the difference between an agonist and a reuptake inhibitor. I wanted to cut her some slack. There are a ton of terms in my own field (software engineering) with very specific meaning, but in casual conversation with other developers those words get used much more loosely.

Disclaimer: This post is in no way criticizing your desire to clarify the issue further - thanks for your contribution! I'm just saying why I chose not to be as particular.

Are you suggesting I might be exhibiting signs of obsessve-compulsive personality disorder? Did I mention that the photos of "brownies" appear to actually be overcooked kladdkaka, a sweedish brownie-like cake and not actual brownies at all?

An agonist actually mimics a neurotransmitter when it binds to a receptor.

Ritalin (methylphenidate) is a norepinephrine-dopamine reuptake inhibitor (more effective with norepinephrine than dopamine) and works by keeping norepinephrine and dopamine in the synaptic gap longer than it normally would have.

Yep which is why unknowingly combining a dopamine reuptake-inhibitor with a dopamine agonist can be particularly problematic and is not strictly an additive effect, part of the reason why the distinction is important.

Just to beat an almost dead horse: I am wondering where the mistake was made (in the study or in the article) because if its the study presumes this, it renders a major "finding" highly questionable.

Not necessarily because both (agonist and reuptake-inhibitor) would cause increases effects equivalent to increased availability and utility of dopamine. Additionally a re-uptake inhibitor would actually be preferable in this sort of experiment because it does not involve introducing a dopamine analog and instead increases availability and utility of the actual dopamine in your nervous system. The can also potentially be made to last longer and far more evenly and consequently make the "spike" easier to measure by both the ERG and a pet scan. That means its at least possible to correlate the measurements made by the ERG with the scans of the brain made by the far slower PET scan even for the same patient. So even if the paper misidentified the drug as either an agonist or antagonist, the drug they used was probably the most appropriate.

What I read is not in the article anymore; its pointless to defend why I thought what I thought it was when it is not now what I think..

Don't forget the Enteric Nervous System, a completely separate nervous system ... it receives considerable innervation from the autonomic nervous system, it can and does operate independently of the brain and the spinal cord, and has been shown to carry the lions share of dopamine production (60-70%) whilst the brain signals carry the smaller productions... Pleasure response is largely below the threshold of our conscience awareness, telling us we are hungry, happy, craving etc.

It was my uncomfortable experience to have an electroretinogram (ERG) for a purpose unrelated to dopamine research. While technically noninvasive, this procedure is extremely unpleasant.

First, your eyes are dilated wide open, and an anesthetic is dripped in. Then contact lenses are inserted. These contact lenses are hard plstic, have tall lips around the edge to prevent you closing your eyes, and a metal post for an electrode wire. You then sit in a pitch-black room for 20 minutes. (This part may be opitonal for the dopamine research). Since you know your eyes are open but you can't see anything, you may suffer the hallucination that the room is not level or is pitching up and down (I did). After this preparation, a light similar to a camera flash is flashed in your eyes every five seconds to perform the actual retinogram measurement. The flash is so bright that it has an almost physical impact, and after just a few flashes, you get really good at anticipating when the next impact will occur.

Did I mention that the contact lenses have lips to prevent you closing your eyes to stop the sensation? While I would not call this sensation pain, it was as unpleasant as a slap in the face. Over and over.

If I had a choice between breaking rocks in tropical sunshine at minimum wage to earn $2,000 for a PET scan, or getting a retinogram for free, it would still depend on whether or not either procedure would save my life. I can tell you that no research budget has enough money in it to pay me to do another ERG.

It was my uncomfortable experience to have an electroretinogram (ERG) for a purpose unrelated to dopamine research. While technically noninvasive, this procedure is extremely unpleasant.

First, your eyes are dilated wide open, and an anesthetic is dripped in. Then contact lenses are inserted. These contact lenses are hard plstic, have tall lips around the edge to prevent you closing your eyes, and a metal post for an electrode wire. You then sit in a pitch-black room for 20 minutes. (This part may be opitonal for the dopamine research). Since you know your eyes are open but you can't see anything, you may suffer the hallucination that the room is not level or is pitching up and down (I did). After this preparation, a light similar to a camera flash is flashed in your eyes every five seconds to perform the actual retinogram measurement. The flash is so bright that it has an almost physical impact, and after just a few flashes, you get really good at anticipating when the next impact will occur.

Did I mention that the contact lenses have lips to prevent you closing your eyes to stop the sensation? While I would not call this sensation pain, it was as unpleasant as a slap in the face. Over and over.

If I had a choice between breaking rocks in tropical sunshine at minimum wage to earn $2,000 for a PET scan, or getting a retinogram for free, it would still depend on whether or not either procedure would save my life. I can tell you that no research budget has enough money in it to pay me to do another ERG.

With a parent currently in his 5th year of Parkinson's disease which is linked to the inability to create dopamine you come to appreciate the vital role dopamine plays in the human body. To witness the effects of the lack of dopamine on your parent is truly heartbreaking so the more that can be learned and understood about the dopamine pathways and the role it plays in the human body can only improve the chances of further drug development to combat this terrible disease.

Are you suggesting I might be exhibiting signs of obsessve-compulsive personality disorder? Did I mention that the photos of "brownies" appear to actually be overcooked kladdkaka, a sweedish brownie-like cake and not actual brownies at all?

By no means, sir, I'd never suggest that a fellow who has a passion for complete and precise knowledge suffered from any disorder!

And who downvoted your comment? Perhaps it was an NSA computer which, lacking any sense of humor, automatically disagreed.

Being pedantic here but dopamine is also an agonist at dopamine receptors. An agonist is any agent that fits the receptor and causes the response. An antagonist in contrast fits the receptor, does not cause a reaction and by blocking the receptor REDUCES the response (for example nalltrexone blocks the action of morphine at mu receptors and can interrupt a narcotic overdose). Some agents fit the receptor and cause a partial response , called, creatively, partial agonists. Agents such as pentazocine fit the mu receptor cause a reaction (relieve some pain) but only to a certain level. Pain thresholds above that are not reached so a higher dose won't relieve more pain (unlike morphine which will continue to relieve greater and greater pain with greater and greater doses). The synapse of course is not nearly so simple. For a relativley simple example see :http://en.wikipedia.org/wiki/Synapse I take exception to the statement regarding the premise of the experiment. If you administer methyphenidate, as mentioned above, it will inhibit reuptake in dopamine synapse junctions (amongst other things, drugs seldom only work at one site) thus increasing the net concentration of dopamine which will cause the reaction they are measuring. However it does not necessarily follow that because a reaction occurs in one tissue it will in another. There are frequently a host of different types of receptors for a given transmitter. So to conclude that because you get extra brain and extra eye dopamine from the drug does not necessarily mean you will get extra dopamine in the brain if you get extra dopamine in the eye system from seeing brownies. Probably, yes. But it does not necessarily follow. A better approach would be to verify with the PET scan procedure while doing the ERG. THEN you could go on to use the ERG to test dopamine levels in the brain.

Hmmmm, according to Biological Psychiatry, A Journal of Psychiatric Neuroscience and Therapeudics. Cannabis users had reduced dopamine synthesis capacity in the striatum and limbic subdivisions compared with control subjects.

Kate Shaw Yoshida / Kate is a science writer for Ars Technica. She recently earned a dual Ph.D. in Zoology and Ecology, Evolutionary Biology and Behavior from Michigan State University, studying the social behavior of wild spotted hyenas.